SCOUT® Radar Localization at Time of Breast Biopsy.

OBJECTIVE: Evaluate surgical utilization of SCOUT reflectors placed at breast biopsy. METHODS: Consent was waived for this retrospective IRB-approved, HIPAA-compliant study. Breast biopsy examinations that reported the term "SCOUT" between January 2021 and June 2022 were identified using an institutional search engine. Cases were included if a SCOUT reflector was placed at time of breast biopsy and excluded if lesion pathology was already known. Analysis was performed at the lesion level. A multivariate-regression analysis evaluated 6 variables with potential impact on SCOUT utilization. RESULTS: One hundred twenty-one lesions in 112 patients met inclusion criteria. Biopsy yielded 93% (113/121) malignant, 3% (4/121) elevated risk, 2% (2/121) benign-discordant, and 2% (2/121) benign-concordant results. Two cases lost to follow-up were excluded. SCOUT reflectors were utilized for lumpectomy (58%, 69/119 lesions) and excisional biopsy (6%, 7/119 lesions). SCOUTs were not utilized due to mastectomy (23%, 27/119), subsequent wire localization (2%, 2/119), and nonsurgical cases (12%, 14/119). Reflector placement utilization was 52% higher for findings less than 3.5 cm in size (P <.001), 33% higher in patients without prior treated breast cancer (P = .012), and 19% higher in patients with no suspicious ipsilateral lymph node (P = .048). CONCLUSION: SCOUT reflector placement at time of biopsy was utilized for surgery 64% (76/119) of the time, although most (98%, 119/121) biopsies were malignant, elevated risk, or benign-discordant. Factors increasing reflector utilization include smaller lesion size, no suspicious ipsilateral lymph node, and no prior treated breast cancer.

Dopamine and its precursor levodopa inactivate SARS-CoV-2 main protease by forming a quinoprotein.

Many studies show either the absence, or very low levels of, SARS-CoV-2 viral RNA and/or antigen in the brain of COVID-19 patients. Reports consistently indicate an abortive infection phenomenon in nervous cells despite the fact that they contain the SARS-CoV-2 receptor, ACE2. Dopamine levels in different brain regions are in the range of micromolar to millimolar concentrations. We have shown that sub-micromolar to low micromolar concentrations of dopamine or its precursor (levodopa) time- and dose-dependently inhibit the activity of SARS-CoV-2 main protease (Mpro), which is vital for the viral life cycle, by forming a quinoprotein. Thiol detection coupled with the assessment of Mpro activity suggests that among the 12 cysteinyl thiols, the active site, Cys145-SH, is preferentially conjugated to the quinone derived from the oxidation of dopamine or levodopa. LC-MS/MS analyses show that the Cys145-SH is covalently conjugated by dopamine- or levodopa-o-quinone. These findings help explain why SARS-CoV-2 causes inefficient replication in many nerve cell lines. It is well recognized that inhaled pulmonary drug delivery is the most robust therapy pathway for lung diseases. CVT-301 (orally inhaled levodopa) was approved by the FDA as a drug for Parkinson's patients prior to the outbreak of COVID-19 in 2018. Based on the fact that SARS-CoV-2 causes inefficient replication in the CNS with abundant endogenous Mpro inhibitor in addition to the current finding that levodopa has an Mpro-inhibitory effect somewhat stronger than dopamine, we should urgently investigate the use of CVT-301 as a lung-targeting, COVID-19, Mpro inhibitor.

Ratio of Red Blood Cell Distribution Width to Albumin Level and Risk of Mortality.

Importance: The ratio of red blood cell distribution width (RDW) to albumin concentration (RAR) has emerged as a reliable prognostic marker for mortality in patients with various diseases. However, whether RAR is associated with mortality in the general population remains unknown. Objectives: To explore whether RAR is associated with all-cause and cause-specific mortality and to elucidate their dose-response association. Design, Setting, and Participants: This population-based prospective cohort study used data from participants in the 1998-2018 US National Health and Nutrition Examination Survey (NHANES) and from the UK Biobank with baseline information provided from 2006 to 2010. Included participants had complete data on serum albumin concentration, RDW, and cause of death. The NHANES data were linked to the National Death Index records through December 31, 2019. For the UK Biobank, dates and causes of death were obtained from the National Health Service Information Centre (England and Wales) and the National Health Service Central Register Scotland (Scotland) to November 30, 2022. Main Outcomes and Measures: Potential associations between RAR and the risk of all-cause and cause-specific mortality were evaluated using Cox proportional hazards regression models. Restricted cubic spline regressions were applied to estimate possible nonlinear associations. Results: In NHANES, 50 622 participants 18 years of age or older years were included (mean [SD] age, 48.6 [18.7] years; 26 136 [51.6%] female), and their mean (SD) RAR was 3.15 (0.51). In the UK Biobank, 418 950 participants 37 years of age or older (mean [SD], 56.6 [8.1] years; 225 038 [53.7%] female) were included, and their mean RAR (SD) was 2.99 (0.31). The NHANES documented 7590 deaths over a median (IQR) follow-up of 9.4 (5.1-14.2) years, and the UK Biobank documented 36 793 deaths over a median (IQR) follow-up of 13.8 (13.0-14.5) years. According to the multivariate analysis, elevated RAR was significantly associated with greater risk of all-cause mortality (NHANES: hazard ratio [HR], 1.83 [95% CI, 1.76-1.90]; UK Biobank: HR, 2.08 [95% CI, 2.03-2.13]), as well as mortality due to malignant neoplasm (NHANES: HR, 1.89 [95% CI, 1.73-2.07]; UK Biobank: HR, 1.93 [95% CI, 1.86-2.00]), heart disease (NHANES: HR, 1.88 [95% CI, 1.74-2.03]; UK Biobank: HR, 2.42 [95% CI, 2.29-2.57]), cerebrovascular disease (NHANES: HR, 1.35 [95% CI, 1.07-1.69]; UK Biobank: HR, 2.15 [95% CI, 1.91-2.42]), respiratory disease (NHANES: HR, 1.99 [95% CI, 1.68-2.35]; UK Biobank: HR, 2.96 [95% CI, 2.78-3.15]), diabetes (NHANES: HR, 1.55 [95% CI, 1.27-1.90]; UK Biobank: HR, 2.83 [95% CI, 2.35-3.40]), and other causes of mortality (NHANES: HR, 1.97 [95% CI, 1.86-2.08]; UK Biobank: HR, 2.40 [95% CI, 2.30-2.50]) in both cohorts. Additionally, a nonlinear association was observed between RAR levels and all-cause mortality in both cohorts. Conclusions and Relevance: In this cohort study, a higher baseline RAR was associated with an increased risk of all-cause and cause-specific mortality in the general population. These findings suggest that RAR may be a simple, reliable, and inexpensive indicator for identifying individuals at high risk of mortality in clinical practice.

Sex-Specific Association Between Childhood Adversity and Accelerated Biological Aging.

Is childhood adversity associated with biological aging, and if so, does sex modify the association, and do lifestyle and mental health mediate the association? A lifespan analysis is conducted using data on 142 872 participants from the UK Biobank to address these questions. Childhood adversity is assessed through the online mental health questionnaire (2016), including physical neglect, physical abuse, emotional neglect, emotional abuse, sexual abuse, and a cumulative score. Biological aging is indicated by telomere length (TL) measured from leukocyte DNA using qPCR, and the shorter TL indicates accelerated biological aging; a lifestyle score is constructed using body mass index, physical activity, drinking, smoking, and diet; mental disorder is assessed using depression, anxiety, and insomnia at the baseline survey. The results reveal a sex-specific association such that childhood adversity is associated with shorter TL in women after adjusting for covariates including polygenic risk score for TL, but not in men. Unhealthy lifestyle and mental disorder partially mediate the association in women. The proportions of indirect effects are largest for sexual and physical abuse. These findings highlight the importance of behavioral and psychological interventions in promoting healthy aging among women who experienced childhood adversity, particularly sexual and physical abuse.

Breast Hemangiomas: Imaging Features With Histopathology Correlation.

Breast hemangiomas are rare benign vascular lesions. In a previously performed review of approximately 10,000 breast surgical pathology results, roughly 0.15% (15/~10 000) were hemangiomas. Hemangiomas are more frequent in women and have a documented age distribution of 1.5 to 82 years. They are most often subcutaneous or subdermal and anterior to the anterior mammary fascia but may rarely be seen in the pectoralis muscles or chest wall. On imaging, breast hemangiomas typically present as oval or round masses, often measuring less than 2.5 cm, with circumscribed or mostly circumscribed, focally microlobulated margins, equal or high density on mammography, and variable echogenicity on US. Calcifications, including phleboliths, can be seen. Color Doppler US often shows hypovascularity or avascularity. MRI appearance can vary, although hemangiomas are generally T2 hyperintense and T1 hypointense with variable enhancement. Pathologic findings vary by subtype, which include perilobular, capillary, cavernous, and venous hemangiomas. If core biopsy pathology results are benign, without atypia, and concordant with imaging and clinical findings, surgical excision is not routinely indicated. Because of histopathologic overlap with well-differentiated or low-grade angiosarcomas, surgical excision may be necessary for definitive diagnosis. Findings that are more common with angiosarcomas include size greater than 2 cm, hypervascularity on Doppler US, irregular shape, and invasive growth pattern.

Analyzing the factors associated with efficacy among teriparatide treatment in postmenopausal women with osteoporosis.

BACKGROUND: Teriparatide (TPTD) is a widely used anabolic agent for the treatment of osteoporosis. Several factors have been identified to be related to bone mineral density (BMD) increase in anti-osteoporosis treatment with other agents; however, there has been no systematic analysis to summarize the associated determinants of BMD reaction to daily teriparatide treatment. METHODS: In this retrospective study, we performed a comprehensive investigation involving not only clinical data but also several relevant lifestyle factors to be examined for their potential contribution to BMD response. This post-hoc analysis included 258 post-menopaused patients with osteoporosis who received TPTD at 20 µg/day for 12 months. Univariate and multivariate analyses were conducted to distinguish the response variables of lumbar spine (LS) BMD transformation, the principal outcome measure of efficacy, from the baseline at 12 months. RESULTS: Twelve months of TPTD treatment resulted in an absolute 0.39 ± 0.37 increase in T-score of LS BMD. Gastrointestinal disease, prior bisphosphonate or glucocorticoid treatment, no vitamin K2 supplementation, low levels of serum 25(OH)D and PINP, weak increment of PINP and ß-CTX at 3 months, unhealthy lifestyle (excessive smoking, tea, coffee, and drinking), vegetarian diet pattern, low ALT level, and high BMD at baseline were determined by univariate analyses to be related to the weak reaction of TPTD treatment (P < 0.10). In the multiple regression model, postmenopausal women with vitamin K2 supplementation, higher baseline serum 25(OH)D level, and higher PINP concentration at 3 months indicated a good reaction of LS BMD at 12 months (P < 0.05). Patients with gastrointestinal disease, prior bisphosphonate and glucocorticoid treatment, vegetarian diet pattern, and higher baseline BMD were significantly more likely to have a lower absolute LS BMD response compared to patients without these characteristics (P < 0.05). Further analysis confirmed the negative effect of unhealthy lifestyle on TPTD treatment. CONCLUSION: Our results emphasize the significance of a comprehensive assessment of clinical or lifestyle-related characteristics of postmenopausal women with osteoporosis in the management of TPTD therapy in routine care.

Endogenous chemicals guard health through inhibiting ferroptotic cell death.

Ferroptosis is a new form of regulated cell death caused by iron-dependent accumulation of lethal polyunsaturated phospholipids peroxidation. It has received considerable attention owing to its putative involvement in a wide range of pathophysiological processes such as organ injury, cardiac ischemia/reperfusion, degenerative disease and its prevalence in plants, invertebrates, yeasts, bacteria, and archaea. To counter ferroptosis, living organisms have evolved a myriad of intrinsic efficient defense systems, such as cyst(e)ine-glutathione-glutathione peroxidase 4 system (cyst(e)ine-GPX4 system), guanosine triphosphate cyclohydrolase 1/tetrahydrobiopterin (BH4) system (GCH1/BH4 system), ferroptosis suppressor protein 1/coenzyme Q10 system (FSP1/CoQ10 system), and so forth. Among these, GPX4 serves as the only enzymatic protection system through the reduction of lipid hydroperoxides, while other defense systems ultimately rely on small compounds to scavenge lipid radicals and prevent ferroptotic cell death. In this article, we systematically summarize the chemical biology of lipid radical trapping process by endogenous chemicals, such as coenzyme Q10 (CoQ10), BH4, hydropersulfides, vitamin K, vitamin E, 7-dehydrocholesterol, with the aim of guiding the discovery of novel ferroptosis inhibitors.

Intercellular Interactions Mediated by HGF And TGF-Β Promote the 3D Spherical and Xenograft Growth of Liver Cancer Cells.

BACKGROUND: Recently, the importance of the interactions between liver cancer cells and fibroblasts has been increasingly recognized; however, many details remain to be explored. METHODS: In this work, we first studied their intercellular interactions using conditioned medium from mouse embryonic fibroblasts (MEFs), then through a previously established coculture model. RESULTS: Culturing in a conditioned medium from MEFs could significantly increase the growth, migration, and invasion of liver cancer cells. The coculture model further demonstrated that a positive feedback loop was formed between transforming growth factor-ß (TGF-ß) from HepG2 cells and mHGF (mouse hepatocyte growth factor) from MEFs during coculture. In this feedback loop, c-Met expression in HepG2 cells was significantly increased, and its downstream signaling pathways, such as Src/FAK, PI3K/AKT, and RAF/MEK/ERK, were activated. Moreover, the proportion of activated MEFs was also increased. More importantly, the growth-promoting effects caused by the interaction of these two cell types were validated in vitro by a 3D spheroid growth assay and in vivo by a xenograft mouse model. CONCLUSION: Collectively, these findings provide valuable insights into the interactions between fibroblasts and liver cancer cells, which may have therapeutic implications for the treatment of liver cancer.

Chemistry and Biology of Podophyllotoxins: An Update.

Podophyllotoxin is an aryltetralin lignan lactone derived from different plants of Podophyllum. It consists of five rings with four chiral centers, one trans-lactone and one aryl tetrahydronaphthalene skeleton with multiple modification sites. Moreover, podophyllotoxin and its derivatives showed lots of bioactivities, including anticancer, anti-inflammatory, antiviral, and insecticidal properties. The demand for podophyllotoxin and its derivatives is rising as a result of their high efficacy. As a continuation of our previous review (Chem. Eur. J., 2017, 23, 4467-4526), herein, total synthesis, biotransformation, structural modifications, bioactivities, and structure-activity relationships of podophyllotoxin and its derivatives from 2017 to 2022 are summarized. Meanwhile, a piece of update information on the origin of new podophyllotoxin analogues from plants from 2014 to 2022 was compiled. We hope that this review will provide a reference for future high value-added applications of podophyllotoxin and its analogues in the pharmaceutical and agricultural fields.

Metabolome subtyping reveals multi-omics characteristics and biological heterogeneity in major psychiatric disorders.

Growing evidence suggests that major psychiatric disorders (MPDs) share common etiologies and pathological processes. However, the diagnosis is currently based on descriptive symptoms, which ignores the underlying pathogenesis and hinders the development of clinical treatments. This highlights the urgency of characterizing molecular biomarkers and establishing objective diagnoses of MPDs. Here, we collected untargeted metabolomics, proteomics and DNA methylation data of 327 patients with MPDs, 131 individuals with genetic high risk and 146 healthy controls to explore the multi-omics characteristics of MPDs. First, differential metabolites (DMs) were identified and we classified MPD patients into 3 subtypes based on DMs. The subtypes showed distinct metabolomics, proteomics and DNA methylation signatures. Specifically, one subtype showed dysregulation of complement and coagulation proteins, while the DNA methylation showed abnormalities in chemical synapses and autophagy. Integrative analysis in metabolic pathways identified the important roles of the citrate cycle, sphingolipid metabolism and amino acid metabolism. Finally, we constructed prediction models based on the metabolites and proteomics that successfully captured the risks of MPD patients. Our study established molecular subtypes of MPDs and elucidated their biological heterogeneity through a multi-omics investigation. These results facilitate the understanding of pathological mechanisms and promote the diagnosis and prevention of MPDs.

Chlorogenic acid as an indispensible partner of caffeic acid in coffee via selective regulation of prooxidative actions of caffeic acid.

Chlorogenic acid (CGA) and caffeic acid (CA) are two major phenolic acids in coffee. Though the International Agency for Research on Cancer has classified CA as a Group2B carcinogen, coffee consumption seems generally safe within the usual levels of intake and is more likely to benefit health than to harm it. We thus speculated that CGA may effectively suppress the carcinogenic potential of CA. In a molar ratio achievable in vivo, this study shows that CGA can inhibit (i) copper reduction caused by CA, (ii) CA oxidation caused by copper, (iii) the formation of hydroxyl radicals by CA and copper, and (iv) DNA damage induced by CA, quercetin or (-)-epigallocatechin-3-gallate in the presence of copper. CA tends to undergo autoxidation to produce hydrogen peroxide and quinone, which further reacts with proteins to form quinoproteins. This autoxidation at a tolerable level normally induces beneficial adaptive responses. This study shows that CGA is less efficient than CA in producing hydrogen peroxide and quinoprotein; however, together they synergistically produce hydrogen peroxide and quinoprotein in vitro at a molar ratio achievable in vivo. In conclusion, CGA can selectively regulate the prooxidant activities of CA depending on whether copper is involved or not. CGA could be viewed as an indispensable partner of CA in coffee, given its dual role in suppressing the carcinogenic potential of CA and boosting CA autoxidation which is beneficial for disease prevention.

Boosting with an aerosolized Ad5-nCoV elicited robust immune responses in inactivated COVID-19 vaccines recipients.

Introduction: The SARS-CoV-2 Omicron variant has become the dominant SARS-CoV-2 variant and exhibits immune escape to current COVID-19 vaccines, the further boosting strategies are required. Methods: We have conducted a non-randomized, open-label and parallel-controlled phase 4 trial to evaluate the magnitude and longevity of immune responses to booster vaccination with intramuscular adenovirus vectored vaccine (Ad5-nCoV), aerosolized Ad5-nCoV, a recombinant protein subunit vaccine (ZF2001) or homologous inactivated vaccine (CoronaVac) in those who received two doses of inactivated COVID-19 vaccines. Results: The aerosolized Ad5-nCoV induced the most robust and long-lasting neutralizing activity against Omicron variant and IFNg T-cell response among all the boosters, with a distinct mucosal immune response. SARS-CoV-2-specific mucosal IgA response was substantially generated in subjects boosted with the aerosolized Ad5-nCoV at day 14 post-vaccination. At month 6, participants boosted with the aerosolized Ad5-nCoV had remarkably higher median titer and seroconversion of the Omicron BA.4/5-specific neutralizing antibody than those who received other boosters. Discussion: Our findings suggest that aerosolized Ad5-nCoV may provide an efficient alternative in response to the spread of the Omicron BA.4/5 variant. Clinical trial registration: https://www.chictr.org.cn/showproj.html?proj=152729, identifier ChiCTR2200057278.

Thrombocytopenia as an important determinant of poor prognosis in patients with pyogenic liver abscess: a retrospective case series.

Background: Thrombocytopenia and poor prognosis in severe conditions are associated. However, the clinical significance of thrombocytopenia in pyogenic liver abscess (PLA) has not been evaluated. Objective: To evaluate the association between thrombocytopenia and the prognosis of patients with PLA. Methods: A consecutive case series of 458 adult patients with PLA hospitalized at Tongji Hospital (Wuhan, China) between October 2011 and June 2021 was included in this cross-sectional analysis. Patient data were compared between the thrombocytopenia and non-thrombocytopenia groups. Multivariate logistic regression, receiver operating characteristic (ROC) curve and propensity score -matched analyses (PSM) were performed. Results: Of the 458 patients with PLA, 94 (20.5%) developed thrombocytopenia, 19 (4.1%) developed septic shock, 14 (3.1%) were admitted to the ICU, and 15 (3.3%) died during hospitalization. Thrombocytopenia was independently associated with shock (95%CI = 3.529-57.944, P < 0.001), ICU admission (95%CI = 1.286-25.733, P = 0.022), and mortality (95%CI = 1.947-34.223, P = 0.004) in multivariate regression analysis. ROC analysis showed that thrombocytopenia may be an identified marker of shock [area under the ROC curve (AUC), 0.8119; cut-off, 92.50; P < 0.0001], ICU admission (AUC, 0.7484; cut-off, 82.50; P < 0.0015), and mortality (AUC, 0.7827; cut-off, 122.50; P < 0.002). These findings remained consistent across 86 pairs of patients analyzed for PSM analyses. Conclusions: Thrombocytopenia is an independent risk factor for poor prognosis in PLA and patients may be more prone to adverse outcomes.

The Interaction between Macrophages and Triple-negative Breast Cancer Cells Induces ROS-Mediated Interleukin 1α Expression to Enhance Tumorigenesis and Metastasis.

Triple-negative breast cancer (TNBC) has higher mortality than non-TNBC because of its stronger metastatic capacity. Increasing studies reported that TNBC tumors had more macrophage infiltration than non-TNBC tumors, which promoted the metastasis of TNBC cells. However, how TNBC cells become more malignant after interacting with macrophages is less reported. In this study, it is observed that when TNBC cells are co-cultured with macrophages, they display higher viability and stronger metastatic ability than non-TNBC cells. Mechanistic studies reveal that TNBC cells acquired these abilities via interactions with macrophages in three phases. First, within 12 h of co-culture with macrophages, some TNBC cells have significantly elevated levels of reactive oxygen species (ROS), which upregulate interleukin 1α (IL1α) expression in ERK1/2-c-Jun- and NF-κB-dependent manners at 24-48 h. Second, the secreted IL1α bound to IL1R1 activates the ERK1/2-ZEB1-VIM pathway which increases metastasis. Third, IL1α/IL1R1 facilitates its own synthesis and induces the expression of IL1ß and IL8 at 72-96 h through the MKK4-JNK-c-Jun and NF-κB signaling pathways. Moreover, a higher level of IL1α is positively correlated with more macrophage infiltration and shorter overall survival in breast cancer patients. Thus, reducing ROS elevation or downregulating IL1α expression can serve as new strategies to decrease metastasis of TNBC.

Preoperative Botulinum Toxin for Abdominal Wall Reconstruction in Massive Hernia Defects-A Propensity-Matched Analysis.

PURPOSE: Reconstruction of massive incisional hernias (IHs) poses a significant challenge with high rates of recurrence. Preoperative chemodenervation using botulinum toxin (BTX) injections in the abdominal wall is a technique that has been used to facilitate primary fascial closure. However, there is limited data directly comparing primary fascial closure rates and postoperative outcomes after hernia repair between patients who do and do not receive preoperative BTX injections. The objective of our study was to compare the outcomes of patients who did and did not receive BTX injections before abdominal wall reconstruction. METHODS: This is a retrospective cohort study including adult patients from 2019 to 2021 who underwent IH repair with and without preoperative BTX injections. Propensity score matching was performed based on body mass index, age, and intraoperative defect size. Demographic and clinical data were recorded and compared. The statistical significance level was set at P < 0.05. RESULTS: Twenty patients underwent IH repair with preoperative BTX injections. Twenty patients who underwent IH repair without preoperative BTX injections were selected to comprise a 1:1 propensity-matched control cohort. The average defect size was 663.9 cm2 in the BTX group and 640.7 cm2 in the non-BTX group (P = 0.816). There was no difference in average age (58.6 vs 59.2 years, P = 0.911) and body mass index (33.0 vs 33.2 kg/m2, P = 0.911). However, there was a greater proportion of male patients in the BTX group (85% vs 55%, P = 0.082).Primary fascial closure was achieved in 95% of BTX patients and 90% of non-BTX patients (P = 1.0). Significantly fewer patients in the BTX group required component separation techniques to achieve primary fascial closure (65% vs 95%, P = 0.044). There was no significant difference in any postoperative surgical and medical outcomes. Hernia recurrence was 10% in the BTX group and 20% in non-BTX group (P = 0.661). CONCLUSIONS: In our study, we observed a lower rate of component separations to achieve primary fascial closure among patients with massive hernia defects who received preoperative BTX injections. These results suggest that preoperative BTX injections may "downstage" the complexity of hernia repair with abdominal wall reconstruction in patients with massive hernia defects and reduce the need for component separation.

Encapsulation of Nano-Bortezomib in Apoptotic Stem Cell-Derived Vesicles for the Treatment of Multiple Myeloma.

Extracellular vesicles (EVs) are lipid bilayer nanovesicles released from living or apoptotic cells that can transport DNA, RNA, protein, and lipid cargo. EVs play critical roles in cell-cell communication and tissue homeostasis, and have numerous therapeutic uses including serving as carriers for nanodrug delivery. There are multiple ways to load EVs with nanodrugs, such as electroporation, extrusion, and ultrasound. However, these approaches may have limited drug-loading rates, poor EV membrane stability, and high cost for large-scale production. Here, it is shown that apoptotic mesenchymal stem cells (MSCs) can encapsulate exogenously added nanoparticles into apoptotic vesicles (apoVs) with a high loading efficiency. When nano-bortezomib is incorporated into apoVs in culture-expanded apoptotic MSCs, nano-bortezomib-apoVs show a synergistic combination effect of bortezomib and apoVs to ameliorate multiple myeloma (MM) in a mouse model, along with significantly reduced side effects of nano-bortezomib. Moreover, it is shown that Rab7 regulates the nanoparticle encapsulation efficiency in apoptotic MSCs and that activation of Rab7 can increase nanoparticle-apoV production. In this study, a previously unknown mechanism to naturally synthesize nano-bortezomib-apoVs to improve MM therapy is revealed.

Preparation and anticancer actions of CuET-nanoparticles dispersed by bovine serum albumin.

Diethyldithiocarbamate-copper complex (CuET) shows promising anticancer effect; nonetheless, preclinical evaluations of CuET are hindered due to poor solubility. We prepared bovine serum albumin (BSA)-dispersed CuET nanoparticles (CuET-NPs) to overcome the shortcoming. Results from a cell-free redox system demonstrated that CuET-NPs reacted with glutathione, leading to form hydroxyl radical. Glutathione-mediated production of hydroxyl radicals may help explain why CuET selectively kills drug-resistant cancer cells with higher levels of glutathione. CuET-NPs dispersed by autoxidation products of green tea epigallocatechin gallate (EGCG) also reacted with glutathione; however, the autoxidation products eradicated hydroxyl radicals; consequently, such CuET-NPs exhibited largely compromised cytotoxicity, suggesting that hydroxyl radical is a crucial mediator of CuET anticancer activity. In cancer cells, BSA-dispersed CuET-NPs exhibited cytotoxic activities equivalent to CuET and induced protein poly-ubiquitination. Moreover, the reported powerful inhibition of CuET on colony formation and migration of cancer cells could be replicated by CuET-NPs. These similarities demonstrate BSA-dispersed CuET-NPs is identical to CuET. Thus, we advanced to pilot toxicological and pharmacological evaluations. CuET-NPs caused hematologic toxicities in mice and induced protein poly-ubiquitination and apoptosis of cancer cells inoculated in mice at a defined pharmacological dose. Given high interest in CuET and its poor solubility, BSA-dispersed CuET-NPs pave the way for preclinical evaluations.

Apoptotic vesicles ameliorate lupus and arthritis via phosphatidylserine-mediated modulation of T cell receptor signaling.

Mesenchymal stem cells (MSCs) influence T cells in health, disease and therapy through messengers of intercellular communication including extracellular vesicles (EVs). Apoptosis is a mode of cell death that tends to promote immune tolerance, and a large number of apoptotic vesicles (apoVs) are generated from MSCs during apoptosis. In an effort to characterize these apoVs and explore their immunomodulatory potential, here we show that after replenishing them systemically, the apoV deficiency in Fas mutant mice and pathological lymphoproliferation were rescued, leading to the amelioration of inflammation and lupus activity. ApoVs directly interacted with CD4+ T cells and inhibited CD25 expression and IL-2 production in a dose-dependent manner. A broad range of Th1/2/17 subsets and cytokines including IFNγ, IL17A and IL-10 were suppressed while Foxp3+ cells were maintained. Mechanistically, exposed phosphatidylserine (PtdSer/PS) on apoVs mediated the interaction with T cells to disrupt proximal T cell receptor signaling transduction. Remarkably, administration of apoVs prevented Th17 differentiation and memory formation, and ameliorated inflammation and joint erosion in murine arthritis. Collectively, our findings unveil a previously unrecognized crosstalk between MSC apoVs and CD4+ T cells and suggest a promising therapeutic use of apoVs for autoimmune diseases.

An adenovirus-vectored RVF vaccine confers complete protection against lethal RVFV challenge in A129 mice.

Instruction: Rift valley fever virus (RVFV) is a mosquito-transmitted bunyavirus that causes severe disease in animals and humans. Nevertheless, there are no vaccines applied to prevent RVFV infection for human at present. Therefore, it is necessary to develop a safe and effective RVFV vaccine. Methods: We generated Ad5-GnGcopt, a replication-deficient recombinant Ad5 vector (human adenovirus serotype 5) expressing codon-optimized RVFV glycoproteins Gn and Gc, and evaluated its immunogenicity and protective efficacy in mice. Results and Discussion: Intramuscular immunization of Ad5-GnGcopt in mice induces strong and durable antibody production and robust cellular immune responses. Additionally, a single vaccination with Ad5-GnGcopt vaccination can completely protect interferon-α/ß receptor-deficient A129 mice from lethal RVFV infection. Our work indicates that Ad5-GnGcopt might represent a potential vaccine candidate against RVFV. However, further research is needed, first to confirm its efficacy in a natural animal host, and ultimately escalate as a potential vaccine candidate for humans.